Optimizing anti-microbial immunity by targeting Sts-1

Project Summary Recent studies have established two homologous phosphatases, Sts-1 and -2, as negative regulators of immune signaling pathways. Interestingly, mice lacking Sts expression (Sts-/-) are profoundly resistant to infection by a number of virulent microbial pathogens, including Candida albicans, Staphylococcus aureus, and Francisella tularensis. Resistance is associated with rapid pathogen clearance, reduced inflammation, and increased survival. The overall goal of this project is to develop new therapeutic strategies that promote enhanced anti- microbial immune responses. The hypothesis to be tested is that drug-mediated inhibition of Sts phosphatase activity will recapitulate the Sts-/- phenotype and lead to beneficial clinical outcomes. Having previously identified high quality Sts-1 inhibitors in a large-scale HTS campaign, this work is expected to produce fully validated lead compounds for subsequent lead optimization. This will be accomplished via three synergistic inter-related Aims: Aim 1: Hit-to-lead optimization of Sts-1 inhibitors. Our working hypothesis is that potent, selective inhibitors of Sts phosphatase activity with favorable ADME can serve as lead series for the development of an innate immune checkpoint inhibitor that enhances antimicrobial immunity. Aim 2: Elucidate Sts intracellular activities and identify promising inhibitory compounds. Our working hypothesis is that drug-mediated inhibition of Sts will upregulate macrophage antimicrobial signaling pathways and effector responses. Aim 3: Role of Sts in vivo and identification of inhibitors with in vivo efficacy. Sts-/- animals are significantly resistant to S. aureus lethal bloodstream infection. Our working hypothesis is that drug-mediated inhibition of Sts activity will recapitulate the Sts-/- antimicrobial resistance phenotype and increase host immunity to S. aureus infection.